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Gene scan of Alzheimer’s families identifies four new suspect genes

More reliable genome-searching tools may give new clues to disease mechanism, therapies

The first family-based
genome-wide association study in Alzheimer’s disease has identified the sites
of four novel genes that may significantly influence risk for the most common
late-onset form of the devastating neurological disorder.In their report in the November 7 American Journal of Human Genetics,
being released online today, a team led by researchers from the MassGeneral
Institute for Neurodegenerative Disease (MGH-MIND) describes how newly
available technology is improving understanding of genetic mechanisms
underlying the disease. The study
presents the first results of the Alzheimer’s Genome Project supported by the
Cure Alzheimer’s Fund and the National Institute of Mental Health.

“Only over the past five
years have we had the tools necessary to identify the full set of genes
influencing susceptibility to late-onset Alzheimer’s, which probably involves
gene-to-gene and gene-to-environment interactions,” says Rudolph Tanzi, PhD,
director of the MGH-MIND Genetics and Aging Research Unit, who led the study.

Adds Lars Bertram, PhD, of
MGH-MIND, co-lead author of the study, “The emergence of gene chips, which
identify markers from the entire genome, along with databases provided by the
Human Genome Project and huge advances in genetic analysis give us the means to
identify genes that previously would not have been considered candidates.”

In the first stage of
their investigation, the researchers tested around a half million DNA markers,
covering most of the human genome, in a National Institutes of Mental Health
(NIMH) sample of more than 400 families in which at least three members were
Alzheimer’s patients.Such family-based
genetic studies are more rigorous and reliable in identifying true gene
associations than those comparing patients with unrelated controls, explains
Christoph Lange, PhD, of the Harvard School of Public Health, the other co-lead
author of the study. “This work demonstrates the value and importance of
family-based design in the area of genome-wide association studies for
genetically complex diseases like Alzheimer’s.”

That analysis found five
markers exhibiting genetic association with Alzheimer’s, one of which
corresponds to the gene for APOE, the only gene firmly established to increase
risk for late-onset Alzheimer’s.To
confirm the four novel sites, the researchers analyzed samples from over 900
additional families.The strongest marker
was located on chromosome 14 and was further supported by an independent
analysis comparing 1,400 Alzheimer’s patients with healthy controls.

“The genetic association of
Alzheimer’s with this novel chromosome 14 gene, which like APOE appears to
influence age of onset, is sufficiently strong to warrant intensive follow-up
investigations into its role in the process of nerve cell death in this
disease,” says Tanzi.“This gene also is
in the general vicinity of the presenilin-1 gene, which we know is an
early-onset Alzheimer’s disease gene.We
don’t know if that proximity is a coincidence, and we currently don’t know what
the new gene does, although there is some indication it may control the
activity of other genes.”

Another of the identified markers
is in a gene known to cause spinocerebellar ataxia, a movement disorder that
involves the death of nerve cells in other parts of the central nervous system,
and a third is in a gene involved with the innate immune system, part of the
body’s defense against bacteria and viruses. The fourth marker is in a gene
that produces a synaptic protein, not surprising, Tanzi notes, since it is
known that loss of synapses correlates well with dementia in Alzheimer’s.

“Virtually all current
research into therapies is based on the Alzheimer’s genes that we already know
about; so each new gene we find not only enhances our ability to predict and
diagnose the disease, but also provides valuable new clues about biochemical
events and pathways involved in the disease process.” adds Tanzi, who was a
co-discoverer of all three of the known early-onset Alzheimer’s genes. He also is the Joseph and Rose Kennedy
Professor of Child Neurology and Mental Retardation at HarvardMedicalSchool.The team is continuing to investigate the
implications of these novel genes as well as the possible impact of less
strongly associated genes also identified in this study.

Massachusetts GeneralHospital, established in
1811, is the original and largest teaching hospital of HarvardMedicalSchool. The MGH conducts
the largest hospital-based research program in the United States, with an annual
research budget of more than $500 million and major research centers in AIDS,
cardiovascular research, cancer, computational and integrative biology,
cutaneous biology, human genetics, medical imaging, neurodegenerative
disorders, regenerative medicine, systems biology, transplantation biology and
photomedicine.